A contribution to the elucidation of the biosynthesis of 3-chloro-4-(3′-chloro-2′-nitrophenyl)-1H-pyrrole (pyrrolnitrin)

Article abstract of DOI:10.1016/j.tetlet.2009.01.034

Selective openings of the ring B of the derivative hexapyrroloindol in basic conditions confirm the rearrangement of the tryptophan to aminoarylpyrrol, analogously to the step catalyzed by the enzyme prnB in the biosynthesis of pyrrolnitrin.

Full text of DOI:10.1016/j.tetlet.2009.01.034

Tetrahedron Letters 50 (2009) 1539–1541
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A contribution to the elucidation of the biosynthesis of
3-chloro-4-(30-chloro-20-nitrophenyl)-1H-pyrrole (pyrrolnitrin)
Ana Bertha Vázquez a, Sylvain Bernès b, Aurelio Ortíz a, Leticia Quintero a, Rosa L. Meza-León a,
*
a Centro de Investigación de la Facultad de Ciencias Químicas, Universidad Autónoma de Puebla, 72570 Puebla, Puebla, Mexico
b Facultad de Ciencias Químicas, UANL, Guerrero y Progreso S/N, Col. Treviño, 64570 Monterrey, N.L., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Selective openings of the ring B of the derivative hexapyrroloindol in basic conditions confirm the rear-
rangement of the tryptophan to aminoarylpyrrol, analogously to the step catalyzed by the enzyme prnB
in the biosynthesis of pyrrolnitrin.
Received 30 October 2008
Revised 21 December 2008
Accepted 9 January 2009
Available online 15 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Selenium derivatives
Pyrrolnitrin
Hexahydropyrroloindole
The antibiotic pyrrolnitrin [3-chloro-4-(30-chloro-20-nitro-
phenyl)-1H-pyrrole] (PRN) 1 (Fig. 1), that is produced by many
pseudomonas, is a secondary metabolite derived from tryptophan
and has strong fungicidal activity.1–4 Two biosynthetic pathways
for PRN from tryptophan were proposed by Van Pée et al.5 and
by Chang et al.6a The first is based mainly on a ring rearrangement
and the second was proposed based on the fate of several specific
carbon and hydrogen isotopic labels during the transformation of
tryptophan to PRN.
In this Letter, we described a novel rearrangement carried out
in (2R,3aR,8aS)-2-phenylselenyl-8-(toluene-4-sulfonyl)-3,3a,8,8a-
hexahydro-2H-pyrrolo[2,3-b]indole-1-carboxylic acid methyl ester
512 using a base as a promoter to provide an aminophenylpyrrole
(APP) derivative 615 as shown in Scheme 1.
The compound 5 was prepared from the commercially available
L
-tryptophan 2 through a series of transformations.12–14 When the
compound 5 is exposed to Brönsted and Lewis acids, the product
isolated of this reaction is ring-opened racemic selenide.12 How-
ever, when this compound was treated with a KOH solution in
water/methanol at reflux temperature for 2 h, unexpectedly pyr-
rolnitrin derivative 6 was achieved in 68% yield as a white solid
compound (mp 128 °C), as shown in Scheme 1.
The rearrangement was explored using different bases and dif-
ferent reaction conditions to furnish the aminophenylpyrrole
derivative 6 (Scheme 2 and Table 1). The KOH was the best base
to carry out this transformation (entry 5). In contrast, when LiOH
was used as base the compound 6 was undetected (entries 3 and
4). Furthermore, the reflux temperature was necessary for the for-
mation of 6. The structure for the compound 615 was confirmed by
Ligon et al.7 have also described four genes, prnABCD, from Pseu-
domonas fluorescens, which encode the biosynthesis of PRN 1 and
described the function of each prn gene product, where the trypto-
phan was identified as the precursor for PRN.4,6
De Laurentis et al.8 have realized the crystallographic character-
ization of prnB, and recently has showed9 the reductive nature of
the gene prnB and that the interaction of L-tryptophan with the
gene is favored in basic conditions.
So far, the transformation catalyzed by prnB has no obvious
chemical precedent. As a consequence, the exact nature of the
compound undergoing the rearrangement to the aminophenylpyr-
role (APP) skeleton as well as the type of reaction leading to its for-
mation is still unclear.
On the other hand, Hino10 described the first synthesis to obtain
cyclic tautomers of tryptophan achieved through the reaction of
Nb-methoxycarbonyl-DL-tryptophan methyl ester with phosphoric
acid at room temperature. This reaction has been the key step to
the preparation of the several natural products.11
Cl
NH
NO2
Cl
1
* Corresponding author. Tel.: +52 222 2295500x7387; fax: +52 222 2295584.
E-mail address: rosaluisa@yahoo.com (R.L. Meza-León).
Figure 1. Pyrrolnitrin (PRN) 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.034

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A. B. Vázquez et al. / Tetrahedron Letters 50 (2009) 1539–1541
CO2Me
CO2H
NH2
N
N
i - iv
v
CO2Me
SePh
N
N
H
Ts
3
2
CO2H
vi
vii
N
CO2Me
CO2Me
N
N
Ts
Ts
4
5
NH
NH
Ts
6
Figure 2. Molecular structure of 6 confirmed by X-ray analysis.
Scheme 1. Reagents and conditions: (i) SOCl2, MeOH; (ii) MeOCOCl; (iii) H3PO3
85%; (iv) TsCl, Py; (v) KOH 1 N MeOH/H2O; (vi) 1-oxa-2-oxo-3-thioindolizinium
chloride, Et3N, PhSeSePh; (vii) KOH, MeOH/H2O.
SePh
SePh
C O
HO
H
C
KOH
N
N
5
X-ray analysis (Fig. 2).16 Interestingly, the conformation stabilized
for 6 in the solid state compares well with that of PRN. A rather low
resolution X-ray study was published for PRN,17 which shows that
the dihedral angle between the pyrrole and the benzene ring is 52°,
very close to that observed in 6: 47.7°. Also, in both cases, mole-
cules are associated in the crystal structure as dimers through
weak intermolecular hydrogen bonds. In the case of 6, centrosym-
metric dimers are formed by N–Hꢀ ꢀ ꢀO bonds involving the pyrrole
NH functionality and one O atom of the SO2 group.
The obtaining of 6 can be explained by the instability of the car-
bamate ion I generated by the hydrolysis which stabilizes produc-
ing CO2, forming a double bond N–C (pyrrole) and breaking the
bond N–C (indole), which lead to the B ring opening. A proton is re-
moved from the II to form the compound III. Finally, an elimination
reaction is carried out to yield 6, as shown in Scheme 3.
A
B
MeOH/H2O
NH
Ts
N
O
Ts
I
II
H
SePh
NH
-H20
-PhSeK
NH
NH
Ts
NH
6
Ts
III
Scheme 3. Possible course of the reaction from 5 to 6.
Acknowledgment
In conclusion, we have found a new rearrangement that was
carried out in (2R,3aR,8aS)-2-phenylselenyl-8-(toluene-4-sulfo-
nyl)-3,3a,8,8a-hexahydro-2H-pyrrolo[2,3-b]indole-1-carboxylic acid
methyl ester 5 promoted by a base to provide the aminophenylpyr-
role (APP) derivative 6, that is, an intermediate of the biosynthesis
of pyrrolnitrin (PRN) 1. Current efforts are being directed toward
the total synthesis of pyrrolnitrin (PRN).
We thank SEP-PROMEP (project) 103.5/06/0959.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.034.
References and notes
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base
5
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Scheme 2. Rearrangement of 5 to formation aminophenylpyrrole (APP) derivative.
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Table 1
Synthesis of the (APP) derivative 6 using different bases
Entry
T (°C)
Base MeOH/H2O
t (h)
Yieldb (%)
Compound
1
2
3
4
5
6
7
Reflux
Room
Reflux
Room
NaOH
NaOH
LiOH
LiOH
KOH
2
48
48
48
1.5
48
1
25
—
—
—
68
—
6
—
—
—
6
—
6
Reflux
Room
KOH
KOH
Room/U.S.a
37
9. De Laurentis, W.; Leang, K.; Hahn, K.; Ross Anderson, J. L.; Adam, A.; Phillips, R.
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a
U.S. ultrasonic.
Purified yield.
b
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A. B. Vázquez et al. / Tetrahedron Letters 50 (2009) 1539–1541
1541
11. (a) Crich, D.; Grant, D.; Krishnamurthy, V.; Patel, M. Acc. Chem. Res. 2007, 40, reduced pressure, and purification was done by chromatography with
a
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5549; (c) Crich, D.; Pavlovic, A. B.; Samy, R. Tetrahedron 1995, 51, 6379–6384.
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3978.
mixture of DCM:hexane, 2:1, to achieve
6
with
a
yield of 68% (32 mg,
0.1290 mmol) like a white solid with a mp of 128 °C. 1H NMR d: 2.37 (3H,
s), 5.99 (1H, d J = 1.5 Hz), 6.58 (1H, d, J = 1.8 Hz), 6.48 (1H, d, J = 2.1 Hz),
7.03–7.28 (5H, m), 7.61 (3H, d, J = 7.2 Hz) 8.46. 13C NMR d: 21.5, 109.3,
113.4, 119.8, 120.1, 122.2, 123.5, 123.7, 124.5, 125.1, 127, 128.2, 142.3;
FAB+MS 313, 154 (base peak) HRMS calcd for C17H16N2O2S [M+] 313.0999,
found 313.1011.
13. Crich, D.; Natarajan, S. J. Org. Chem. 1995, 60, 6237–6241.
14. (a) Bruncko, M.; Crich, D.; Samy, R. Heterocycles 1993, 36, 1735–1738; (b) Crich,
D.; Chan, C.-O.; Davies, J. W.; Natarajan, S.; Vinter, J. G. J. Chem. Soc., Perkin
Trans. 2 1992, 2233–2240; (c) Crich, D.; Bruncko, M.; Natarajan, S.; Teo, B. K.;
Tocher, D. A. Tetrahedron 1995, 51, 2215–2228.
16. Colorless crystals, P21/c, a = 8.8157(12), b = 12.172(3), c = 14.7456(16) Å,
b = 101.886(7)°. Data (4858 reflections) collected with the Mo-K
a radiation
15. Preparation of 6. Compound 5 (0.1 g 0.1894 mmol) was dissolved in a 2 N
KOH solution in H2O/MeOH, 7:3, and refluxed for about 120 min. The
reaction was followed by TLC until the starting material disappeared. The
workup was done with 20 mL of 10% HCl solution, extraction with 20 mL of
DCM (three times), drying with Na2SO4, concentration was done under
at 298 K (Bruker P4 diffractometer) and corrected for absorption effects. The
structure was refined without restraints; data to parameters ratio: 2740/206;
Final R1 residual for 2111 Fo > 4r(Fo): 0.040. Further details may be found in the
archived CIF, deposition number: CCDC 707014.
17. Morimoto, Y.; Hashimoto, M.; Hattori, K. Tetrahedron Lett. 1968, 2, 209–211.